Transdermal patches are gaining wide acceptance in the medical community as a desirable means to deliver physiologically active substances. Transdermal patches allow the patient to receive an approximately constant supply of medication over an extended period of time, without the need to dose himself. A patient will, in general, however, not tolerate a patch that is too large or that is uncomfortable or irritating to the skin. This irritation is particularly evident when physiologically active amines in the free base form such as chlorpheniramine, diphenhydramine or dexbrompheniramine are placed on the skin.
Transdermal patches must be capable of administering the required daily dose of the substance. The slower the transdermal flux rate of the active substance, the larger the patch must be to deliver the appropriate amount of substance to satisfy the dosage requirement. In general, transdermal patches should be less than 20 to 25 square centimeters, and more usually, less than 6 square centimeters. Therefore, there is an absolute lower limit in transdermal flux rate for each active substance or composition to be able to administer it in the form of a patch of reasonable size.
It is known that physiologically active amines in their nonionized form in general penetrate the skin easily and quickly (i.e., have a high transdermal flux rate). In fact, physiologically active amines in the nonionized form are generally considered to be the fastest traveling passive, transdermally diffusing compounds known (Michaels, A. S., Chandrasekaran, S. K., Shaw, J. E., Drug permeation through human skin: theory and in vitro experimental measurement. A.I.Ch.E.J., 1975, 21, 985-996.). Physiologically active free amines, however, are often very irritating when administered through the skin (i.e., transdermally), often causing blisters, erythma, pruritus, and burning. Examples of transdermal patches that exhibit these topical adverse effects include the Habitrol.TM. and Prostep.TM. transdermal systems for the systemic delivery of nicotine, which is a tertiary amine. Prior art compositions that have been formulated to reduce the irritating property of the amine free base, have done so at the expense of a significant reduction in the transdermal flux rate of the pharmaceutical composition. This significant reduction in transdermal flux rate decreases the usefulness of the composition in a transdermal patch, because of the large size of the patch needed to deliver an appropriate amount of the active substance. As an example, physiologically active amines such as chlorpheniramine can be delivered in the form of maleate (HO.sub.2 CCH=CHCO.sub.2 H) salts. The maleate salt of the amine is significantly less irritating than the uncomplexed physiologically active amine, as noted in Table 1 of the application. Maleate amine salts, however, travel so slowly through the skin that they are typically not useful for transdermal delivery. The same is true of water soluble salicylate salts of amines.
Physiologically active amines in the free base form have also been provided in a number of pharmaceutically acceptable carriers, including nonpolar solvents. However, the amines were either: (1) nonirritating to begin with; (2) were delivered in their irritating state; or (3) were complexed as salts that have unsuitably low flux rates for transdermal patch delivery. For example, European Patent Application No. 0 262 753 teaches a transdermal delivery system that includes a physiologically active amine, scopolamine, dissolved in a solvent such as mineral oil or isopropyl myristate. This reference does not teach how to reduce the irritation of the uncomplexed amine on delivery. French Patent Application No. 2 397 190 discloses that clonidine can be transdermally administered in a nonpolar solvent. This reference also does not address how to complex the amine to reduce irritation. British Application No. 2 140 019 discloses a drug delivery system that includes an active amine in a mineral oil. As with the other two applications, this reference does not address how to prepare a formulation that minimizes irritation.
WO 86/00806 is directed to the identification of an antihistaminic drug that is nonirritating and that has a suitably high flux rate. The inventors attacked this problem by screening the irritation and flux rate of a number of antihistaminic amines (see Table 1 of the reference). They identified one agent, azatadine, that was nonirritating and that had a suitably high flux rate. The WO 86/00806 publication, on page 7, states that "It is surprising to find that after numerous antihistamines were tested, there was only one antihistamine, azatadine, that had good dermal penetration and no dermal irritation or sensitization." This reference highlights the need for a method and composition to administer an irritating physiologically active amine in a nonirritating formulation that provides a suitably high transdermal flux rate.
U.S. Pat. No. 2,735,799 discloses a method of making an epinephrine composition that protects the epinephrine from oxidation. The patent discloses the use of the HCI, bitartrate, sulfate, and borate salts (see column 1, lines 25-28). These physiologically active amine salts are unsuitable for transdermal delivery because they are water soluble salts and would have low transdermal flux rates.
U.S. Pat. No. 3,304,230 discloses that a salt formed between a water soluble amine and a C.sub.4 to C.sub.18 monocarboxylic acid is soluble in volatile aerosol repellant fluids and still retains water solubility (see column 1, lines 58-72, and column 2, lines 26-36). The patent is not directed to compositions for controlled transdermal delivery, but instead, to volatile aerosol compositions for inhalation. The patent does not teach or suggest haw to formulate physiologically active amines in a manner that minimizes skin irritation while maintaining a high transdermal flux rate.
U.S. Pat. No. 4,690,683 to Chien, et al., discloses a transdermal varapamil delivery device that includes the active material in a bioacceptable lipophilic polymer that contains an effective amount of the active drug and an effective amount of a transport enhancing agent. The Chien reference teaches that the preferred transport enhancing agents are isopropyl myristate, n-decylmethylsulfoxide, oleyl alcohol, propyl oleate, 1-dodecylazacycloheptan-2-one, and N,N-diethyl-m-toluamide. Other transport enhancing materials listed by Chien include thioglycolate salts, fatty alcohols, saturated and unsaturated fatty acids, glycol monoesters of fatty acids, and fatty acid monoglycerides. Chien also discloses that a combination of these materials can be used, for example, isopropyl myristate (a fatty ester) and N,N-diethyl-m-toluamide (an amide). The patent teaches that to maintain the proper pH for delivery, an acid such as disodium hydrogen phosphate/citric acid can be incorporated into the adhesive. This patent does not appear to address how to minimize the irritability of the composition.
Given the convenience of transdermal patches as a means for the delivery of normally irritating physiologically active amines, and the ability of the patches to provide a constant supply of medication over an extended period of time without the need for periodic dosages, it would be of great benefit to have a method and composition that minimizes irritation without serious compromise of the transdermal flux rate.
Therefore, it is an object of the present invention to provide a method and composition for the transdermal, percutaneous or local administration of physiologically active amines to humans in a manner that minimizes skin irritation while maintaining a high transdermal flux rate.